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1.
Cancer Sci ; 115(5): 1505-1519, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38476010

RESUMO

The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.


Assuntos
Adenocarcinoma de Pulmão , Fibroblastos Associados a Câncer , Indóis , Neoplasias Pulmonares , Proteína Smad3 , Inibidor Tecidual de Metaloproteinase-1 , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Humanos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Camundongos , Indóis/farmacologia , Indóis/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Proteína Smad3/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino
2.
Bioorg Med Chem Lett ; 99: 129627, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38272189

RESUMO

Metastasis is one of the major causes of death in patients with cancer, and cell invasion plays a fundamental part in this process. Because of the absence of efficacious treatments, caring for these patients is challenging. Recently, we optimized the structure of the naturally occurring lasso peptide sungsanpin. We identified two peptides, octapeptide S3 and cyclic peptide S4, which inhibited invasion into A549 cells effectively. We undertook an alanine scan of S3 to explore the structure-activity relationship. The linear octapeptide S3-4 and cyclic peptide S4-1 exhibited improved inhibition of invasion into A549 cells. We modified S3-4 to obtain S3-4K, which displayed much higher inhibitory activity against invasion into A549 cells than S3-4. Of all peptides tested, S4-1 upregulated significantly mRNA of tissue inhibitor matrix metalloproteinase TIMP-1 and TIMP-2.


Assuntos
Peptídeos , Inibidor Tecidual de Metaloproteinase-1 , Humanos , Inibidor Tecidual de Metaloproteinase-1/genética , Metaloproteinases da Matriz , Células A549 , Peptídeos Cíclicos
3.
Cell Biochem Funct ; 42(2): e3958, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38396357

RESUMO

Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.


Assuntos
Acetilcisteína , Sobrecarga de Ferro , Oligopeptídeos , Animais , Masculino , Ratos , Acetilcisteína/farmacologia , Acetilcisteína/metabolismo , Caspases/metabolismo , Claudinas/genética , Giro Denteado/metabolismo , Giro Denteado/patologia , Dextranos/metabolismo , Dextranos/farmacologia , Regulação para Baixo , Glutationa/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Ferro/metabolismo , Ferro/farmacologia , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/farmacologia , Nestina/genética , Nestina/metabolismo , Nestina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Regulação para Cima , Oligopeptídeos/farmacologia , Heme Oxigenase-1/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo
4.
Int J Mol Sci ; 25(11)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38891934

RESUMO

Despite the significant changes that unfold during the subacute phase of stroke, few studies have examined recovery abilities during this critical period. As neuroinflammation subsides and tissue degradation diminishes, the processes of neuroplasticity and angiogenesis intensify. An important factor in brain physiology and pathology, particularly neuroplasticity, is matrix metalloproteinase 9 (MMP-9). Its activity is modulated by tissue inhibitors of metalloproteinases (TIMPs), which impede substrate binding and activity by binding to its active sites. Notably, TIMP-1 specifically targets MMP-9 among other matrix metalloproteinases (MMPs). Our present study examines whether MMP-9 may play a beneficial role in psychological functions, particularly in alleviating depressive symptoms and enhancing specific cognitive domains, such as calculation. It appears that improvements in depressive symptoms during rehabilitation were notably linked with baseline MMP-9 plasma levels (r = -0.36, p = 0.025), and particularly so with the ratio of MMP-9 to TIMP-1, indicative of active MMP-9 (r = -0.42, p = 0.008). Furthermore, our findings support previous research demonstrating an inverse relationship between pre-rehabilitation MMP-9 serum levels and post-rehabilitation motor function. Crucially, our study emphasizes a positive correlation between cognition and motor function, highlighting the necessity of integrating both aspects into rehabilitation planning. These findings demonstrate the potential utility of MMP-9 as a prognostic biomarker for delineating recovery trajectories and guiding personalized treatment strategies for stroke patients during the subacute phase.


Assuntos
Metaloproteinase 9 da Matriz , Acidente Vascular Cerebral , Inibidor Tecidual de Metaloproteinase-1 , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/metabolismo , Humanos , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Masculino , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/sangue , Feminino , Estudos Prospectivos , Idoso , Recuperação de Função Fisiológica , Pessoa de Meia-Idade , Reabilitação do Acidente Vascular Cerebral , Biomarcadores/sangue
5.
Int J Mol Sci ; 25(12)2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38928311

RESUMO

Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no satisfactory or clinically effective pharmaceutical treatments for this condition. Accelerated inflammatory processes during aneurysm development lead to increased levels of matrix metalloproteinases (MMPs) and destabilization of the vessel wall through the degradation of the structural components of the extracellular matrix (ECM), mainly collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) directly regulate MMP activity and consequently inhibit ECM proteolysis. In this work, the synthesis of TIMP-1 protein was increased by the exogenous delivery of synthetic TIMP-1 encoding mRNA into aortic vessel tissue in an attempt to inhibit MMP-9. In vitro, TIMP-1 mRNA transfection resulted in significantly increased TIMP-1 protein expression in various cells. The functionality of the expressed protein was evaluated in an appropriate ex vivo aortic vessel model. Decreased MMP-9 activity was detected using in situ zymography 24 h and 48 h post microinjection of 5 µg TIMP-1 mRNA into the aortic vessel wall. These results suggest that TIMP-1 mRNA administration is a promising approach for the treatment of aneurysms.


Assuntos
Metaloproteinase 9 da Matriz , RNA Mensageiro , Inibidor Tecidual de Metaloproteinase-1 , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Humanos , Ratos , Aneurisma/terapia , Aneurisma/genética , Aorta/metabolismo , Masculino , Artérias/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia
6.
J Cell Physiol ; 238(8): 1876-1890, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37269543

RESUMO

Epithelial keratinocyte proliferation is an essential element of wound repair, and chronic wound conditions, such as diabetic foot, are characterized by aberrant re-epithelialization. In this study, we examined the functional role of retinoic acid inducible-gene I (RIG-I), a key regulator of epidermal keratinocyte proliferation, in promoting TIMP-1 expression. We found that RIG-I is overexpressed in keratinocytes of skin injury and underexpressed in skin wound sites of diabetic foot and streptozotocin-induced diabetic mice. Moreover, mice lacking RIG-I developed an aggravated phenotype when subjected to skin injury. Mechanistically, RIG-I promoted keratinocyte proliferation and wound repair by inducing TIMP-1 via the NF-κB signaling pathway. Indeed, recombinant TIMP-1 directly accelerated HaCaT cell proliferation in vitro and promoted wound healing in Ddx58-/- and diabetic mice in vivo. In summary, we demonstrated that RIG-I is a crucial factor that mediates epidermal keratinocyte proliferation and may be a potential biomarker for skin injury severity, thus making it an attractive locally therapeutic target for the treatment of chronic wounds such as diabetic foot.


Assuntos
Diabetes Mellitus Experimental , Pé Diabético , Animais , Camundongos , Movimento Celular , Proliferação de Células , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Pé Diabético/genética , Pé Diabético/metabolismo , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Pele/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Cicatrização/genética
7.
Neurobiol Dis ; 179: 106057, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36878326

RESUMO

The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Camundongos , Humanos , Animais , Idoso , Apolipoproteína E4/genética , Memória de Curto Prazo , Apolipoproteína E3/genética , Camundongos Transgênicos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Receptores CCR5
8.
Kidney Int ; 103(1): 144-155, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273656

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) involves the development and persistent growth of fluid filled kidney cysts. In a recent study, we showed that ADPKD kidney cyst epithelial cells can stimulate the proliferation and differentiation of peri-cystic myofibroblasts. Although dense myofibroblast populations are often found surrounding kidney cysts, their role in cyst enlargement or fibrosis in ADPKD is unclear. To clarify this, we examined the effect of myofibroblast depletion in the Pkd1RC/RC (RC/RC) mouse model of ADPKD. RC/RC;αSMAtk mice that use the ganciclovir-thymidine kinase system to selectively deplete α-smooth muscle actin expressing myofibroblasts were generated. Ganciclovir treatment for four weeks depleted myofibroblasts, reduced kidney fibrosis and preserved kidney function in these mice. Importantly, myofibroblast depletion significantly reduced cyst growth and cyst epithelial cell proliferation in RC/RC;αSMAtk mouse kidneys. Similar ganciclovir treatment did not alter cyst growth or fibrosis in wild-type or RC/RC littermates. In vitro, co-culture with myofibroblasts from the kidneys of patients with ADPKD increased 3D microcyst growth of human ADPKD cyst epithelial cells. Treatment with conditioned culture media from ADPKD kidney myofibroblasts increased microcyst growth and cell proliferation of ADPKD cyst epithelial cells. Further examination of ADPKD myofibroblast conditioned media showed high levels of protease inhibitors including PAI1, TIMP1 and 2, NGAL and TFPI-2, and treatment with recombinant PAI1 and TIMP1 increased ADPKD cyst epithelial cell proliferation in vitro. Thus, our findings show that myofibroblasts directly promote cyst epithelial cell proliferation, cyst growth and fibrosis in ADPKD kidneys, and their targeting could be a novel therapeutic strategy to treat PKD.


Assuntos
Cistos , Rim Policístico Autossômico Dominante , Humanos , Camundongos , Animais , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , Miofibroblastos , Células Cultivadas , Rim/patologia , Proliferação de Células , Fibrose , Cistos/tratamento farmacológico , Cistos/patologia , Células Epiteliais/patologia
9.
J Neuroinflammation ; 20(1): 151, 2023 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-37365625

RESUMO

BACKGROUND: Epilepsy is the second most prevalent neurological disease. Although there are many antiseizure drugs, approximately 30% of cases are refractory to treatment. Temporal lobe epilepsy (TLE) is the most common epilepsy subtype, and previous studies have reported that hippocampal inflammation is an important mechanism associated with the occurrence and development of TLE. However, the inflammatory biomarkers associated with TLE are not well defined. METHODS: In our study, we merged human hippocampus datasets (GSE48350 and GSE63808) through batch correction and generally verified the diagnostic roles of inflammation-related genes (IRGs) and subtype classification according to IRGs in epilepsy through differential expression, random forest, support vector machine, nomogram, subtype classification, enrichment, protein‒protein interaction, immune cell infiltration, and immune function analyses. Finally, we detected the location and expression of inhibitor of metalloproteinase-1 (TIMP1) in epileptic patients and kainic acid-induced epileptic mice. RESULTS: According to the bioinformatics analysis, we identified TIMP1 as the most significant IRG associated with TLE, and we found that TIMP1 was mainly located in cortical neurons and scantly expressed in cortical gliocytes by immunofluorescence staining. We detected decreased expression of TIMP1 by quantitative real-time polymerase chain reaction and western blotting. CONCLUSION: TIMP1, the most significant IRG associated with TLE, might be a novel and promising biomarker to study the mechanism of epilepsy and guide the discovery of new drugs for its treatment.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Humanos , Camundongos , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Biomarcadores/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
10.
BMC Gastroenterol ; 23(1): 287, 2023 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-37605137

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) is one of the leading causes of peptic ulcers, and its treatment is a worldwide challenge. Matrix metalloproteinases and their inhibitors influence the development and healing of peptic ulcers. This study aimed to evaluate the ratios of matrix metalloproteinase-2 (MMP-2) to tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with peptic ulcers that are sensitive or resistant to H. pylori treatment and compare them with healthy individuals. METHODS: In this study, 95 patients were included and divided into two groups sensitive (41 patients) and resistant to treatment (54 patients). The results were compared with a control group of 20 participants with normal endoscopy and H. pylori-negative. After obtaining written informed consent, five ml of venous blood was taken to determine their serum MMP-2 and TIMP-1 levels using an enzyme-linked immunosorbent assay. RESULTS: In patients with H. pylori-induced peptic ulcers, the MMP-2/TIMP-1 ratio was significantly higher than the healthy controls (P < 0.05). MMP-2 level was associated with patients' response to treatment (P < 0.05). The MMP-2/TIMP-1 ratio was higher in patients with simultaneous gastric and duodenal ulcers (P < 0.05). CONCLUSION: It seems that peptic ulcer disease caused by infection with H. pylori increases the MMP-2/TIMP-1 ratio in patients with peptic ulcers. However, it might not be a good predictor of refractory H. pylori-induced peptic ulcer disease.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Úlcera Péptica , Humanos , Inibidor Tecidual de Metaloproteinase-1 , Metaloproteinase 2 da Matriz , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Úlcera Péptica/tratamento farmacológico
11.
J Biochem Mol Toxicol ; 37(11): e23453, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37437075

RESUMO

Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality. Here, we aimed to explore the roles and potential correlation of placenta polypeptide injection (PPI) and MMP-9/TIMP-1 signaling pathway in COPD. BEAS-2B cells were treated with cigarette smoke extract (CSE) to establish a COPD cell model in vitro. The cell survival and cytotoxic effect were measured by CCK-8, LDH release and flow cytometry assays. The inflammatory responses were determined by western blot and ELISA assay. Cell fibrosis was assessed by immunofluorescence and western blot assays. PPI treatment had no cytotoxic effect on BEAS-2B cells until the final concentration reached to 10%. In the range of 0%-8% final concentration, PPI treatment weakened CSE-induced the decrease of cell viability and the increase of LDH level in a concentration-dependent manner. Four percent PPI treatment enhanced cell viability and decreased cell apoptosis of CSE-treated cells in a time-dependent manner. Moreover, 4% PPI treatment significantly decreased inflammatory responses and fibrosis induced by CSE, while AMPA (MMPs agonist) had opposite effects. Notably, AMPA reversed the protective roles of PPI on CSE-induced inflammation and fibrosis. Mechanistically, 4% PPI treatment significantly suppressed MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-19 levels, but enhanced TIMP-1, TIMP-2, TIMP-3, and TIMP-4 levels. Among them, MMP-9 and TIMP-1 might be the main target of PPI. PPI effectively attenuated CSE-induced inflammation and fibrosis in vitro by regulating MMP-9/TIMP-1 signaling pathway.


Assuntos
Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Humanos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Transdução de Sinais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Peptídeos/efeitos adversos
12.
BMC Pulm Med ; 23(1): 32, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690987

RESUMO

OBJECTS: The family with sequence similarity 83B (FAM83B) is one of the markers for poor prognosis in several carcinomas, but the expression and the mechanism resulted in malignant phenotype in lung adenocarcinoma (LUAD) remain to be elucidated. METHODS:  Data of RNA-seq in LUAD were downloaded from the cancer genome atlas (TCGA) database for differential expression and survival analysis, and immunohistochemistry was employed to analyze the protein expression of FAM83B in 126 cases of primary LUAD. The LUAD cell lines were collected for the detection of the effects on migration and invasion. Then, western blot was performed to measure the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and activation of PI3K/AKT/NF-κB pathway. RESULTS: FAM83B was overexpressed in multiple types of carcinomas; The differential expression analysis revealed that the level of FAM83B was higher in LUAD than that in para-carcinoma; The patients with overexpression of FAM83B were with shorter overall survival (OS), disease specific survival (DSS) and progress free interval (PFI); Enrichment analysis suggested it was related to the focal adhesion of LUAD. Immunohistochemistry analysis demonstrated that higher FAM83B expression was positively related to lymph node metastasis in primary. Scratch assay and Borden chamber assay showed that the overexpression of FAM83B promoted migration and invasion activity in vitro. Furthermore, high level of FAM83B accelerated the tumorigenesis in vivo. Western blot showed that TIMP-1 was upregulated in H1299/FAM83B OE cells accompanying by the activation of PI3K/AKT/NF-κB pathway. CONCLUSIONS: FAM83B was a marker for poor prognosis of LUAD and it might promote the expression of TIMP-1 by activating PI3K/AKT/NF-κB pathway and then affect the ECM balance, which resulted in the migration and invasion of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética
13.
Eur J Appl Physiol ; 2023 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-38043087

RESUMO

OBJECTIVES: The objectives of this study were to assess the effect of 8 weeks of moderate-intensity aerobic training on permeability inflammatory indicators of matrix metalloproteinases (MMPs) and specific tissue inhibitors of MMPs in female migraineurs. METHODS: Female migraineurs (n = 28, age 32 ± 6) were randomised into two groups: migraine with exercise training (EXE + Mig, n = 13) and migraine without exercise training (NON-EXE + Mig, n = 15). Matched healthy women were also recruited as a healthy control group (CON, n = 15). The EXE-Mig group performed 8 weeks of aerobic training. Pre and post intervention, serum matrix metalloproteinases (MMP-2 and 9) and specific tissue inhibitors of MMPs (TIMP-1 and 2) were measured. In addition, body composition indices and VO2max were determined. RESULTS: Exercise training reduced serum MMP-9 in female migraineurs with between-group changes and a time x group interaction (p < 0.05). In addition, exercise training reduced the serum MMP-9/TIMP-1 ratio in female migraineurs with between-group changes and time x group interaction (p < 0.05). However, no training-induced effect was observed in serum TIMP-1, TIMP-2, MMP-2 contents (p > 0.05) and MMP-2/TIMP-2 ratio (p > 0.05). Finally, exercise training reduced body fat content, WHR and BMI, and improved VO2max (p < 0.01). CONCLUSIONS: Our results demonstrated beneficial effects of aerobic exercise training on some circulatory inflammation factors (MMP9, MMP-9/TIMP-1) and some health indicators in female migraineurs, suggesting that such training can be employed as a non-pharmacological therapeutic method.

14.
BMC Musculoskelet Disord ; 24(1): 240, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36991363

RESUMO

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) are involved in the pathological mechanism of osteonecrosis of the femoral head (ONFH). This study aimed to investigate the relationship of serum MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio with disease severity in patients with nontraumatic ONFH. METHODS: Serum levels of MMP-9 and TIMP-1 among 102 nontraumatic ONFH patients and 96 healthy individuals were determined by enzyme-linked immunosorbent assay (ELISA). Imaging severity was determined using the FICAT classification system. The Harris hip score (HHS) and visual analogue scale (VAS) were used to evaluate clinical progress. The correlations of serum MMP-9 and TIMP-1 levels with imaging severity and clinical progress was evaluated statistically. The diagnostic value of MMP-9 for NONFH disease severity was evaluated by examining receiver operating characteristic (ROC) curves. RESULTS: The serum MMP-9 levels and the MMP-9/TIMP-1 ratio were significantly increased in patients with ONFH compared to normal controls, and TIMP-1 levels did not differ between the two groups. Serum MMP-9 levels and the MMP-9/TIMP-1 ratio were positively correlated with FICAT stage and VAS and were negatively correlated with the HHS score. The ROC curve results indicated that MMP-9 could be used as a potential marker of nontraumatic ONFH imaging progression. CONCLUSIONS: We hypothesize that increased MMP-9 expression and an imbalance in the MMP-9/TIMP-1 ratio play a role in the development of ONFH and are correlate with the severity of ONFH. The determination of MMP-9 can be a useful tool to assess the severity of the disease in patients with nontraumatic ONFH.


Assuntos
Necrose da Cabeça do Fêmur , Metaloproteinase 9 da Matriz , Humanos , Cabeça do Fêmur/patologia , Metaloproteinase 9 da Matriz/sangue , Curva ROC , Inibidor Tecidual de Metaloproteinase-1/sangue , Necrose da Cabeça do Fêmur/sangue
15.
Proc Natl Acad Sci U S A ; 117(5): 2588-2596, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31969449

RESUMO

Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Neoplasias Pulmonares/enzimologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Humanos , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 14 Ativada por Mitógeno/genética , Processos Neoplásicos , Proteínas Proto-Oncogênicas p21(ras)/genética
16.
Biochem Genet ; 2023 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-38103125

RESUMO

Angiogenesis is the critical media for tumor growth and migration. Tissue Inhibitor Matrix Metalloproteinase-1 (TIMP1) acts as an oncogene in colon carcinoma (CC), but the biological effects of TIMP1 on angiogenesis remain an open issue. This study sought to explore the exact function and mechanism of TIMP1 in the angiogenesis of CC. Bioinformatics methods were utilized to analyze the expression of TIMP1 and its upstream transcription factor FOS-like antigen 1 (FOSL1) in the tumor tissue of CC. Meanwhile, in CC cell lines, real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were utilized to verify the expression of TIMP1 and FOSL1. Cell counting kit-8 and tube formation assays were utilized to analyze the proliferation and angiogenesis abilities of human umbilical vein endothelial cells (HUVECs). Western blot was used to detect the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out to explore the specific interaction between FOSL1 and TIMP1. The present study discovered that TIMP1 and FOSL1 were evidently up-regulated in CC tissue and cells. Meanwhile, TIMP1 was found to participate in regulating the signaling pathway of vascular endothelial growth factor (VEGF). Silenced TIMP1 conspicuously suppressed the proliferation and angiogenesis of HUVECs and reduced the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Moreover, FOSL1 could promote TIMP1 transcription by binding with its promoter and the inhibition of TIMP1 expression obviously reversed the promotion effects of FOSL1 overexpression on the proliferation and angiogenesis of HUVECs. FOSL1 activated VEGF pathway by up-regulating TIMP1 expression, thereby advancing CC angiogenesis. We provided theoretical basis that the FOSL1/TIMP1/VEGF pathway might be a novel option for anti-angiogenesis therapy of CC.

17.
Immunopharmacol Immunotoxicol ; 45(4): 419-425, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36541209

RESUMO

BACKGROUND: Ferroptosis is involved in the drug resistance mechanisms of some tumors. The present study aimed to explore the role of tissue inhibitor of matrix metalloprotease 1 (TIMP1) in sorafenib-triggered ferroptosis in colorectal cancer (CRC). METHODS: HCT-8 CRC cell lines were generated that were sorafenib-resistant or that under- or overexpressed TIMP1. The levels of reactive oxygen species (ROS), iron, and malondialdehyde (MDA) were compared across the different cell lines. The half-maximal inhibitory concentration of sorafenib against the different lines was determined based on cell viability. Expression of ferroptosis-related genes and the corresponding proteins was determined by quantitative RT-PCR or western blotting. RESULTS: TIMP1 overexpression induced sorafenib resistance in HCT-8 cells. TIMP1 knockdown repressed the activation of the PI3K/Akt pathway and reduced levels of glutathione peroxidase 4 (GPX4), enhancing sorafenib-induced ferroptosis. This led to accumulation of ROS, iron, and MDA. Giving sorafenib and the GPX4 inhibitor RSL3 to sorafenib-resistant HCT-8 cells induced ferroptosis, leading to elevated levels of iron and lipid peroxides, ultimately reducing cell viability. TIMP1 depletion in CRC cells enhances sorafenib-triggered ferroptosis by reducing PI3K/Akt axis signal transduction. CONCLUSION: The combination of sorafenib and GPX4 inhibitors such as RSL3 may be a promising therapy against CRC.


Assuntos
Neoplasias Colorretais , Ferroptose , Transdução de Sinais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Ferro , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Espécies Reativas de Oxigênio , Sorafenibe/farmacologia , Inibidor Tecidual de Metaloproteinase-1
18.
Chem Biodivers ; 20(2): e202201221, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36651671

RESUMO

Cancer metastasis, including cell invasion, is a major cause of poor clinical outcomes and death in numerous cancer patients. In recent years, many efforts have been made to develop potent therapeutic molecules from naturally derived peptides. Sungsanpin is a naturally derived lasso peptide that inhibits A549 cell invasion. We aimed to evaluate the potential of sungsanpin derivatives as candidates for anti-invasion drugs. We synthesized an analog of sungsanpin (Sun A) using a solid-phase peptide synthesis strategy (SPPS) and further modified its structure to improve its anti-invasion activity. All peptides were tested for their proliferative inhibition and anti-invasion activities in the A549 cell lines. Octapeptide S3 and cyclooctapeptide S4 upregulated the expression of TIMP-1 and TIMP-2 mRNA effectively and thus improved the inhibitory effect on the invasion of A549 cells. The two peptides can inhibit the invasion of A549 cells by up to 60 %, suggesting that they have potential as lead molecules for the development of peptide inhibitors.


Assuntos
Neoplasias Pulmonares , Peptídeos , Humanos , Peptídeos/química , Células A549 , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico
19.
Int J Neurosci ; : 1-15, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38060511

RESUMO

INTRODUCTION: Granule cell dispersion (GCD) is pathognomonic of hippocampal sclerosis seen in the mesial temporal lobe epilepsy (MTLE). Current animal studies indicate deficiency of Reelin is associated with abnormal granule cell migration leading to GCD. The present study aimed to evaluate complete Reelin signalling pathway to assess whether Reelin deficiency is related to MTLE. MATERIALS AND METHODS: Hippocampal sclerosis was confirmed by H and E stain. To explore the amount and cellular location of the Reelin cascade molecules, the hippocampal tissues from MTLE surgery and controls (n = 15 each) were studied using Immuno-histochemistry (IHC). Additionally, confocal imaging was used to validate the IHC findings by co-localization of different proteins. Quantification of IHC images was performed using histo-score and confocal images by Image J software. RESULTS: Immune expression of active Reelin was significantly reduced in patients. Reelin receptors were deranged, apolipoprotein E receptor 2 was increased while very low-density lipoprotein receptor was reduced. Disabled-1, a downstream molecule was significantly reduced in MTLE. Its ultimate target, cofilin was thus disinhibited and expressed more in MTLE. Reelin cleaving protease, matrix metalloprotease-9 (MMP-9) and MMP-9 inhibitor, tissue inhibitor of matrix protease-1, showed reduced expression in extracellular matrix. Semi-quantification of immunohistochemistry was done using Histo (H) score. H score of Reelin in diseased patients was 15 against 125 for control patients. These results were validated by confocal fluorescence microscopy. CONCLUSIONS: Reelin signalling cascade was deranged in chronic MTLE. Pharmacological manipulation of Reelin cascade can be done at various levels and it may provide novel treatment options for MTLE.

20.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675165

RESUMO

Acute lung injury is a complex cascade process that develops in response to various damaging factors, which can lead to acute respiratory distress syndrome. Within this study, based on bioinformatics reanalysis of available full-transcriptome data of acute lung injury induced in mice and humans by various factors, we selected a set of genes that could serve as good targets for suppressing inflammation in the lung tissue, evaluated their expression in the cells of different origins during LPS-induced inflammation, and chose the tissue inhibitor of metalloproteinase Timp1 as a promising target for suppressing inflammation. We designed an effective chemically modified anti-TIMP1 siRNA and showed that Timp1 silencing correlates with a decrease in the pro-inflammatory cytokine IL6 secretion in cultured macrophage cells and reduces the severity of LPS-induced acute lung injury in a mouse model.


Assuntos
Lesão Pulmonar Aguda , RNA Interferente Pequeno , Animais , Humanos , Camundongos , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Fenótipo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
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